Mutations in chs1/beige result in a deficiency in intracellular transport of vesicles that leads to a generalized immune deficiency in mouse and man. The function of NK cells, CTL, and granulocytes is impaired by these mutations indicating that polarized trafficking of vesicles is controlled by chs1/beige proteins. However, a molecular explanation for this defect has not been identified.
Lipopolysaccharide (LPS) is a potent inducer of maturation in B cells, monocytes, and dendritic cells that facilitates production of inflammatory cytokines, nitric oxide, and antigen presentation so that these cells can participate in the immune response to bacterial pathogens (Harris, M. R. et al. Journal of Immunology, 1984, 133:1202; Tobias, P.S. et al. Progress in Clinical & Biol. Res., 1994, 388:31; Inazawa, M. et al. Lymphokine Res., 1985, 4:343). In an attempt to identify genes involved in the maturation of immune cells, a gene-trapping strategy was developed to identify mammalian genes whose expression is altered by cellular stimuli (Kerr, W. G. et al. Cold Spring Harbor Symposia on Quantitative Biology, 1989, 54:767). Several novel LPS-responsive genes were successfully trapped (Kerr, W. G. et al. Proc. Natl. Acad. of Sci. USA, 1996, 93:3947), including the SHIP gene that plays a role in controlling the maturation and proliferation of B cells and monocytes/macrophages in vivo (Huber, M. et al. Prog. in Biophysics and Molecular Biol., 1999, 71:423; Ono, M. et al. Nature, 1996, 383:263; Ono, M. et al. Cell, 1997, 90:293).
Chediak-Higashi Syndrome (CHS3) patients suffer from a systematic immune deficiency characterized by a severe immune defect, hypopigmentation, progressive neurologic dysfunction and a bleeding diathesis (Spritz, R. A. Jour. of Clinical Immun., 1998, 18:97). Specific defects in immune cells include defects in T cell cytotoxicity (Abo, T. et al. Jour. of Clinical Investigation, 1982, 70:193; Baetz, K. et al. Jour. of Immun., 1995, 154:6122), killing by NK cells (Haliotis, T. et al. Jour. of Exper. Med., 1980, 151:1039), defective bactericidal activity and chemotaxis by granulocytes and monocytes (Clark, R. A. and H. R. Kimball Jour. of Clinical Investigation, 1971, 50:2645). CHS and beige lysosomes also exhibit compartmental missorting of proteins (Takeuchi, K. et al. Jour. of Exper. Med., 1986, 163:665). Other studies have found that beige macrophages are defective for class II surface presentation (Faigle, W. et al. J. Cell Biol., 1998, 141:1121; Lem, L. et al. Jour. of Immun., 1999, 162:523) and that T cells in CHS patients are defective for CTLA4 surface expression (Barrat, F. J. et al. Proc. Natl. Acad. of Sci. USA, 1999, 96:8645). All cells in beige mice and CHS patients bear giant vesicles that cluster around the nucleus. Affected vesicles include lysosomes, platelet dense granules, endosomes, and cytolytic granules. These giant vesicles seem normal in several aspects except for their failure to release their contents, probably resulting from inability of the giant granules to mobilize and/or fuse with the membrane upon stimulation (Baetz, K. et al. Jour. of Immun., 1995, 154:6122). However, despite these very provocative findings there still remains no direct evidence that BG(beige)/CHS1 proteins associate with intracellular vesicles and thus a molecular explanation for defective vesicle trafficking and protein missorting in these diseases is still sought.